Multiple reports suggest that acceptance and use of opioid medicines for relief of chronic pain are increasing substantially, and that opioidergic medications (especially in high doses) and chronic pain each perturb neuroendocrine functions, particularly those of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes. In addition, numerous well-controlled analgesic trials attest to the high frequency and importance of the placebo effect in the treatment of pain. Several investigations suggest that neuroendocrine alterations underly the biology of the placebo effect. The latter observation is made more provocative by recent neuroimaging studies suggesting that placebo analgesia is associated with activation of similar anatomic components of the cortex as with bona fide analgesic intake. To date, however, there has been little systematic inquiry comparing the effects of chronic (versus acute) pain, conventional (versus high) dose opioid use and placebo administration on neureoendocrine function, pain symptomatology, or quality of life in a well-defined population of individuals with chronic musculoskeletal pain. Thus, the objectives of the current study are to evaluate, in middle-aged men with chronic musculoskeletal pain due to osetoarthritis (OA), the effects of chronic OA pain per se versus long-term opioid usage on neuroendocrine function (ACTH, cortisol, LH and testosterone secretion), pain symptomatology, mood and quality of life, and whether placebo analgesia results in similar, albeit soemwhat lesser, effects on on neuroendocrine function, pain symptomatology, mood and quality of life as those elicited by an opioid analgesic. To address these questions, we have initiated a 4-part study. In part I, 12 narcotic naive men with chronic osteoarthritis (OA) pain will be comapred with 12 healthy, age- and BMI-matched men by assessing 12 hour overnight q 20 min blood sampling for measurements of ACTH, cortisol, LH and testosterone, as well as measures of pain symptomatology, mood and QOL. In part II, 36 narcotic naive patients with chronic OA pain (including the 12 men above), all of whom will have undergone overnight hormone sampling and neuropsychological evaluations in Part I, will be randomized to one of three treatment groups: MS Contin (15-90 mg), placebo or ?standard treatment? with NSAID's. Doses of placebo and MS Contin will be escalated over 4 weeks in a similar fashion with two-week maintenance and 2 week taper. At the end of maintenance at 6 weeks, all patients will return for repeat 12 hour frequent sampling and neuropsychological studies as in Part I. At the end of part II, patients are invited to go on to an open label treatment period (Part III) with MS Contin (15-120 mg), which will consist of a 6-week dose escalation and 8 weeks of maintenance on opioid medication. At the conclusion of Part III, patients will be seen in outpatient clinic, and undergo AM endocrine testing and repeat neurpopsychologcal assessment. They will then be referred back to their physicians with recommendations for continued treatment with MS Contin, if patients are interested in this option. In Part IV of the study, patients will be followed by telephone for 6 months, after which they will be asked to return for an outpatient assessment like that at the end of Part III. The primary endpoints of this study will be measures of ACTH, cortisol, LH, and testosterone secretion, whereas the secondary endpoints will include selected neurobehavioral indices of pain and bothersomeness symptomatology, and measures of mood and quality of life. It is anticipated that this study will provide novel information regarding the effects of chronic musculoskeletal pain, and treatment with opioids versus placebo, on selected neuroendocrine functions in men. Recruitment for this study began on 11/1/04, with considerable success to date. As of 9/15/05, 114 opioid naive OA patients have been phone screened, 22 have completed out-patient screeening visits, 15 have completed Part I, 13 have completed Part II, 12 have completed Part III and 4 have finished Part IV. 39 healthy men were phone screened, 13 underwent screening visits, and 12 have completed Part I.